title: A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion.
abstract: BACKGROUND
  Dual oxidases (DUOX1 and DUOX2) play a crucial role in the generation of hydrogen peroxide required in the oxidation of iodide and the synthesis of thyroid hormone. Heterodimerization with specific maturation factors (DUOXA1 and DUOXA2) is essential for the maturation and function of the DUOX enzyme complexes. Biallelic loss-of-function mutations of DUOX2 result in congenital hypothyroidism (CH), whereas a single reported case of homozygous DUOXA2 mutation (Y246X) has been associated with mild CH.
  
  
  OBJECTIVE
  We now report an infant with transient CH due to a complex genetic alteration of the DUOX/DUOXA system.
  
  
  RESULTS
  Our patient was born to euthyroid nonconsanguineous parents and presented with an elevated TSH and enlarged thyroid gland at neonatal screening. Genetic analysis revealed a missense mutation (C189R) on the maternal DUOXA2 allele. The mutant DUOXA2 protein showed complete loss-of-function in reconstituting DUOX2 in vitro. The apparent C189R homozygosity of the proband in the absence of the same mutation in the father led to detailed gene mapping, revealing an approximately 43-kb pair deletion encompassing DUOX2, DUOXA1, and DUOXA2. Thus, in addition to being deficient in DUOXA2, the proband lacks one allele of DUOX2 and DUOXA1 but has two functioning DUOX1 alleles.
  
  
  CONCLUSIONS
  The transient CH in the presence of only one functional maturation factor allele indicates a high level of functional redundancy in the DUOX/DUOXA system.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Imge
authors.initials: I
authors.lastname: Hulur
authors.forename: Pia
authors.initials: P
authors.lastname: Hermanns
authors.forename: Claudia
authors.initials: C
authors.lastname: Nestoris
authors.forename: Sabine
authors.initials: S
authors.lastname: Heger
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Joachim
authors.initials: J
authors.lastname: Pohlenz
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
mesh_terms: D000483:Alleles; D015153:Blotting, Western; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D000074623:Dual Oxidases; D017353:Gene Deletion; D018628:Gene Dosage; D005822:Genetic Vectors; D006579:Heterozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000473:pathology; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013972:Thyrotropin / Q000097:blood; D014162:Transfection
chemical_list: C513411:DUOXA2 protein, human; D008565:Membrane Proteins; D013972:Thyrotropin; D004247:DNA; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human